A novel form of long term synaptic depression (LTD) has been identified in the hippocampus associated with acute pharmacological increases in protein O-GlcNAc levels (O-linkage of N-acetylglucosamine to S/R residues of target proteins). Initial characterization of this LTD reveals an NMDA- and PKC-independent form of plasticity with strong evidence for postsynaptic AMPA receptor internalization at CA3-CA1 synapses mediated by direct O-GlcNAcylation of the GluA2 subunit. The current proposal is designed to test the hypothesis that the phenomenon of O-GlcNAc LTD can be applied therapeutically to neuronal hyperactivity to reduce epileptoform activity during seizures. We further hypothesize that the circuit dampening effects of increased O-GlcNAc and the synaptic LTD represent a shared expression mechanism of AMPA receptor internalization from CA1 dendrites. The small but growing list of synaptic proteins shown to undergo O- GlcNAcylation suggests that this cell signaling system plays a critical role in normal synaptic transmission and may serve further regulatory function during periods of pathological neuronal network activity. The experimental findings outlined in this proposal will serve as further characterization of the role of O-GlcNAc a CNS synapses, and examination of the protein O-GlcNAcylation as a possible therapeutic target.